PROJECT SUMMARY Alzheimer's disease (AD) is a disease of aging. AD is the most common form of dementia, afflicting more than 5 million Americans aged 65 and older. By 2050 it is estimated that more than 14 million Americans will suffer this disease, and that its direct financial impact will exceed $1.1 trillion. AD is particularly burdensome because it impairs memory; it worsens with time; and there is no cure. Sleep disruption in AD is highly prevalent, and changes in sleep architecture and circadian rhythmicity that result in excessive daytime sleepiness and nighttime insomnia are well documented. Less well known is the impact of sleep or circadian disruption on the etiology of the disease. Sleep facilitates A? clearance from brain, and sleep disruption increases A? in cerebrospinal fluid. A? pathology impairs core clock genes and exacerbates neuroinflammation. Collectively, these data suggest that sleep and circadian disruption induce responses that feed forward and contribute to, or exacerbate AD pathology and accelerate disease progression. However, to our knowledge definitive studies to determine the extent to which sleep disruption per se contributes to AD pathology have not been conducted. We will use mice expressing an inducible mutant amyloid precursor protein (APP) transgene to temporally dissociate sleep disruption and mutant APP expression from subsequent A? deposition and AD-like pathology. Specifically, we will: 1) determine how chronic sleep disruption of transgenic mice alters the course of pathology induced by expression of mutant APP; 2) determine if sleep disruption accelerates AD onset; and 3) target a key mediator of innate immune activation and determine effects on responses to sleep disruption and/or mutant APP expression. Outcome measures for each aim include assessments of cognitive performance; synaptic plasticity; differential gene expression; glial activation; cytokine production; neuroinflammatory signaling; and proteinopathy. Our multidisciplinary research team has demonstrated expertise and possesses all requisite skills to successfully complete the proposed project. Successful completion of this project will have a sustained impact on the field because we will elucidate the extent to which, and potential mechanisms by which, chronic sleep disruption alters the progression of AD-like pathology.